A system and a corresponding method for estimating respiratory drive of mechanically ventilated patients

ABSTRACT

The present invention relates to a system ( 10 ) and a corresponding method for estimating the respiratory drive (R_DRIVE) of mechanically ventilated patients, and for preferably apportioning this respiratory drive into one, or more, components related to the chemical drive—i.e. the drive due to the chemoreceptor response—and/or the muscular drive—i.e. the contraction of respiratory muscles, for example the diaphragm. The principle of the invention is that respiratory drive can be obtained from measuring the patient&#39;s response to small changes in mechanical ventilation settings (Vt_SET), and that this can be apportioned into chemical and/or muscular effects depending upon the changes in respiratory frequency, and/or arterial or end tidal CO 2  levels, and/or arterial blood p H.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a system and a corresponding method forestimating the respiratory drive of mechanically ventilated patients.More particularly, for apportioning this respiratory drive into one, ormore, components related to chemical drive—i.e. the drive due to thechemoreceptor response—and/or muscular drive—i.e. the contraction ofrespiratory muscles, for example the diaphragm.

BACKGROUND OF THE INVENTION

Patients residing at the intensive care unit typically receivemechanical support for their ventilation. Selecting the appropriatelevel of mechanical ventilation is not trivial, and it has been shownthat appropriate settings can reduce mortality [1].

Notice that a device or system capable of performing mechanicalventilation is sometimes called an artificial breathing machine, a lifesupport device, or, more popularly, a respirator.

Typically, patients are ventilated using “support” modes. In thesemodes, patients have some respiratory drive and try to breathethemselves, with the patient then being “supported” with extrainspiratory volume or pressure. The patient's respiratory drive iscontrolled, primarily, by two factors.

The first factor is the signalling from the brain to the respiratorymuscles that they should contract such that a breath is taken. Thissignaling is due to a number of factors but paramount in these is thechemical signaling by the chemoreflex system. Adverse changes in oxygen,carbon dioxide and acid levels of blood and cerebral spinal fluid (CSF)are detected by the body chemoreceptors, which signal the brain tochange the rate and depth of breathing. In health this signaling will beappropriate to normalize levels of oxygen, carbon dioxide and acidity ofthe blood and CSF. In disease, or in other situations such as theadministration of opioids and other drugs, chemoreceptor response may bereduced, and signaling insufficient. The chemical response to breathingis also modified by metabolism, such that a greater respiratory drivewill be present in situations of higher CO₂ production; and insituations where the acid-base status of blood or CSF is acutely orchronically changed. For example, the chronic changes in the bufferingproperties of CSF in patients with chronic lung disease are well knownto reduce chemical drive to breathing via central chemoreceptorresponse.

The second factor is the nature of the muscles. In health, signals fromthe brain to the respiratory muscles that a breath is required, wouldresult in contraction of the respiratory muscles by the appropriateamount to ensure ventilator volumes, which normalize levels of oxygen,carbon dioxide and acidity of the blood and CSF. In disease, therespiratory muscles may be weakened or tired and as such unable tocontract the appropriate amount.

The degree to which patients on mechanical ventilation should besupported depends upon their respiratory drive i.e. their own capabilityto control respiration. Patients with reduced drive will require extrasupport through greater volume or pressure levels. Patients with morenormal levels of drive could receive reduced support, potentiallyenabling then to be weaned from mechanical ventilation more quickly. Asweaning takes up a large portion of the time spent on mechanicalventilation[2], rapid appropriate weaning may be very beneficial. Hence,improved methods for estimating respiratory drive would be advantageous.

A deeper understanding of the reasons for reduced respiratory drivecould also be beneficial. Reduced chemical drive could lead the doctorto consider reducing opioid therapy. Reduced muscular drive could leadthe doctor to consider mobilisation of the patient. Hence, improvedmethods for apportioning respiratory drive to components related tochemical and/or muscular drive would be advantageous.

US patent application 2010/0228142 (invented by Christer Sinderby,assigned to Maquet Critical Care) discloses a method for determiningdynamically a respiratory feature in a spontaneously breathing patientreceiving mechanical ventilatory assist. The method comprises: modifyinga level of mechanical ventilatory assist to the patient, measuring anairway pressure, detecting a change of gradient of the measured airwaypressure and determining the respiratory feature based on the measuredairway pressure upon detecting the change of gradient of the airwaypressure. Furthermore, the method also comprises: measuring arespiratory neural drive of the patient and detecting a lowest level ofthe measured respiratory neural drive for determining the respiratoryfeature based on the detected lowest level of respiratory neural drive.An inherent disadvantage by this method is the need for measuring neuraldrive by an electrode in the diaphragm which is typically inserted intothe oesophagus.

Hence, an improved way of estimating respiratory drive would beadvantageous, and in particular a more efficient and/or reliable way ofestimating respiratory drive would be advantageous.

SUMMARY OF THE INVENTION

A system and a corresponding method are presented where baseline valuesof, or changes in the values of volume support or pressure support, in amechanically ventilated patient, and measurement of the response inventilator parameters, such as respiratory frequency, are used toestimate the patient's respiratory drive, and preferably to apportionthis drive into one, or more, components related to chemical andmuscular response. In this way, a greater understanding of the patientcan be obtained during mechanical ventilation, which may improvediagnosis and the selection of mechanical ventilator settings.

Thus, an object of the present invention relates to a system and amethod for estimating the total respiratory drive of a patient fromchanges in mechanical ventilator settings.

Thus, one object of the invention relates to a system and a method forapportioning a component of the respiratory drive due to chemicalresponse from chemoreceptors.

Thus, a further object of the invention relates to a system and a methodfor apportioning a component of the respiratory drive due to muscularresponse for the respiratory muscles.

In a first aspect, the present invention relates to a mechanicalventilation system for respiration aid of an associated patient, thesystem being adapted for estimating one, or more, components of therespiratory drive (R_DRIVE) of said patient, the system comprising:

-   -   ventilator means (VENT) capable of mechanical ventilating said        patient with air and/or one or more medical gases,    -   control means (CON), the ventilator means being controllable by        said control means by operational connection thereto, and    -   measurement means (M_G) arranged for measuring the respiratory        feedback of said patient in the expired gas in response to the        mechanical ventilation, the measurement means being capable of        delivering first data (D1) to said control means,        wherein the control means is capable of operating the        ventilation means by providing ventilatory assistance so that        said patient is at least partly breathing spontaneously, and,        when providing such ventilatory assistance, the control means        being capable of changing one, or more, volume and/or pressure        parameters (Vt_SET) of the ventilator means so as to detect        changes in the respiratory feedback of said patient by the        measurement means,        the control means further being arranged for receiving second        data (D2), preferably obtainable from blood analysis of said        patient, said second data being indicative of the respiratory        feedback in the blood of said patient,        the control means being adapted for using:    -   the first data (D1) indicative of changes of respiratory        feedback in expired air, and    -   the second data (D2) indicative of the respiratory feedback in        the blood, in a physiological model (MOD) capable of estimating        one, or more, components (R_MUSC, R_CHEM) of the total        respiratory drive (R_DRIVE) for the patient.

The principle of the invention presented here is that measurement ofchanges ventilation frequency or volume in response to changesventilator support settings can be used, in combination withmathematical physiological models, to identify chemoreceptor drive,muscular drive and/or the total respiratory drive which is beneficial toobtain for diagnostic and/or curative purposes.

Advantageously, the physiological model (MOD) may comprise a componentof the total respiratory drive being indicative of muscular response(R_MUSC). This is an advantage because previously the muscular responsecould be difficult to measure or evaluate. Alternatively oradditionally, the physiological model (MOD) may comprise a component ofthe total respiratory drive being indicative of chemical response(R_CHEM), preferably a subcomponent indicative of the central chemicalresponse and a subcomponent indicative of the peripheral chemicalresponse. The chemical response of the respiratory drive is typicallythe dominating factor and is therefore important to evaluate.Beneficially, the control means may be arranged for estimating both themuscular response (R_MUS) and chemical response (R_CHEM) forming part ofthe total respiratory drive (R_DRIVE).

In another embodiment of the mechanical ventilation system, themeasurement means and the control means may be further arranged tomeasure an indication of muscular response (R_MUSC), such as byestimating or obtaining muscular drive from other measurement means orsources (e.g. previous values), such as an electrical measurement of thediaphragm, or similar.

In an embodiment, the control means may be arranged for estimating themuscular response (R_MUS) and chemical response (R_CHEM) by initiallyassuming one of the two responses; muscular response (R_MUS) or chemicalresponse (R_CHEM), being a certain approximately constant level,preferably a normal level for said patient depending on the medicalhistory and/or condition of the patient, and then subsequentlyiteratively solving for the other response, e.g. assuming normalmuscular response and then solve for the chemical response as it will beexplained below. In one particular embodiment of this, the mechanicalventilation system may assume that the muscular response is initiallyconstant, preferably a normal level for said patient, and the chemicalresponse may then be estimated, the estimated chemical response beingsubsequently applied for modelling a respiratory feedback to be comparedwith a measured respiratory feedback of the patient, this feedback beingcharacterised by for example changes in respiratory volume or frequency,or measures of oxygenation or acid base-status of blood, or respiratorygasses. Any deviation between model simulated and measured feedbackbeing an absolute or relative measure for an inadequate responsecapability of the patient. The said inadequate response capability ofthe patient may at least be a measure of the fatigue of the patient,though the inadequate response capability of the patient could also beinterpreted to be a measure, or a component, of other reasons for poorrespiratory muscle function such as medication with for example musclerelaxants, or other medications which reduce respiratory responsethrough action on non-chemoreceptor mechanisms.

In one embodiment, the second data (D2) used in the physiological model(MOD) may be indicative for oxygenation and/or acid-base status of theblood, e.g. pHa, preferably being related to the influence of theacid-base status on the cerebrospinal fluid (CSF). In anotherembodiment, the second data (D2) used in the physiological model (MOD)may, alternatively or additionally, be indicative for the metabolism ofsaid patient, preferably the tissue production of carbon dioxide (CO₂).

In one particular embodiment, the physiological model (MOD) capable ofestimating one, or more, components of the total respiratory drive(R_DRIVE) for the patient may be operationally connected to a medicaldecision support system (DSS), preferably for application in mechanicalventilation. The DSS could be applied in connection with treatment plan,for therapy, and/or for diagnosis of the patient. As an example, the DSScould be the so-called INVENT system co-developed by one of the presentinventors, cf. reference [5] and [6], these references being herebyincorporated by reference in their entirety.

In another particular embodiment, the measurement means (M_G) may bearranged for measuring one or more of the following parametersconsisting of: respiratory frequency (RR) or, equivalently, duration ofbreath (including duration of inspiratory or expiratory phase), andexpiratory carbon dioxide levels (FECO₂), fraction of carbon dioxide inexpired gas at the end of expiration, (FE′CO₂), partial pressure ofcarbon dioxide in expired gas (PECO₂), partial pressure of carbondioxide in expired gas at the end of expiration (PE′CO₂), or equivalentsthereof and/or combinations thereof. Other parameters applicable forrespiratory response or feedback by a patient measurable in the expiredair may also be applied within the context of the present invention oncethe general principle and teaching of the invention has been appreciatedby the skilled person.

In another embodiment, the second data (D2), which may be obtainablefrom blood analysis (M_B) of said patient (P), may be one or moreparameters consisting of: arterial blood pH (pHa), pressure of carbondioxide level (PaCO₂), optionally measured transcutaneously (PtcCO₂),oxygen saturation of arterial blood (SaO₂), pressure of oxygen inarterial blood (PpO₂), or equivalents thereof and/or combinationsthereof. Other parameters applicable, estimated or measurable in bloodof a patient may also be applied within the context of the presentinvention once the general principle and teaching of the invention hasbeen appreciated by the skilled person.

Particularly, the present invention is advantageous in that therespiratory drive may be estimated without using a measurement of theelectrical activity of the diaphragm of the patient, cf. US patentapplication 2010/0228142 where this is performed.

In a beneficial embodiment, the control means (CON) may be capable ofchanging the level from one value to another value in one, or more,volume and/or pressure parameters of the ventilator means (Vt_SET) so asto detect the subsequent changes in the respiratory feedback of saidpatient by the measurement means. Thus, the changes of ventilatorsetting are made and afterwards the respiratory feedback of the patientis measured.

Beneficially, the control means may be alternatively be capable ofperforming a change in one, or more, volume and/or pressure parametersof the ventilator means (Vt_SET) so as to detect associated changes inthe respiratory feedback of said patient by the measurement means whileperforming said change. Thus, the changes of Vt_SET are made whilechanges in respiration are simultaneously measured.

In one embodiment, wherein the control means may be capable of changingone, or more, volume and/or pressure parameters of the ventilator meansby changing the inspiratory volume (Vt_SET) and/or the inspiratorypressure set by the ventilator means. It is important to distinguishbetween the settings for pressure or volume for the mechanicalventilator, and, on the other hand, the actual volume inhaled or expiredby the patient, as it will be understood by a person skilled inmechanical ventilation of patients.

In a second aspect, the present invention relates to method foroperating a mechanical ventilation system for respiration aid of anassociated patient, the method being adapted for estimating one, ormore, components of the respiratory drive (R_DRIVE) of said patient, themethod comprising:

-   -   providing ventilator means (VENT) capable of mechanical        ventilating said patient with air and/or one or more medical        gases,    -   providing control means (CON), the ventilator means being        controllable by said control means by operational connection        thereto, and    -   providing measurement means (M_G) arranged for measuring the        respiratory feedback of said patient in the expired gas in        response to the mechanical ventilation, the measurement means        being capable of delivering first data (D1) to said control        means,        wherein the control means is capable of operating the        ventilation means by providing ventilatory assistance so that        said patient is at least partly breathing spontaneously, and,        when providing such ventilatory assistance, the control means        being capable of changing one, or more, volume and/or pressure        parameters (Vt_SET) of the ventilator means so as to detect        changes in the respiratory feedback of said patient by the        measurement means,        the control means further being arranged for receiving second        data (D2), preferably obtainable from blood analysis of said        patient, said second data being indicative of the respiratory        feedback in the blood of said patient,        the control means being adapted for:    -   applying the first data (D1) indicative of changes of        respiratory feedback in expired air, and    -   applying the second data (D2) indicative of the respiratory        feedback in the blood,        in a physiological model (MOD) capable of estimating one, or        more, components (R_MUSC, R_CHEM) of the total respiratory drive        (R_DRIVE) for the patient.

In a third aspect, the present invention relates to a computer programproduct being adapted to enable a computer system comprising at leastone computer having data storage means in connection therewith tocontrol a ventilation system according to the first and/or secondaspect. Thus, this aspect of the invention may differ from the method ofthe second aspect in that the third aspect is directed to controllingand/or cooperating with the ventilator means (VENT), the control means(CON), and measurement means (M_G) i.e. instead of providing them.

This aspect of the invention is particularly, but not exclusively,advantageous in that the present invention may be accomplished by acomputer program product enabling a computer system to carry out theoperations of the ventilation system of the first aspect of theinvention when down- or uploaded into the computer system. Such acomputer program product may be provided on any kind of computerreadable medium, or through a network.

The individual aspects of the present invention may each be combinedwith any of the other aspects. These and other aspects of the inventionwill be apparent from the following description with reference to thedescribed embodiments.

BRIEF DESCRIPTION OF THE FIGURES

The method according to the invention will now be described in moredetail with regard to the accompanying figures. The figures show one wayof implementing the present invention and is not to be construed asbeing limiting to other possible embodiments falling within the scope ofthe attached claim set.

FIG. 1 is a schematic drawing of a mechanical ventilation systemaccording to the present invention,

FIG. 2 is a schematic flow chart of a physiological model applied in thepresent invention,

FIG. 3 is a model simulated response of a patient to changes inventilator support,

FIG. 4 shows three graphs using data collected from a single patientshowing the results of the present invention in the graphs,

FIG. 5 shows seven graphs using data collected from a single patientshowing the results of the present invention in the graphs,

FIG. 6 illustrates the set of mathematical model components of adecision support system (DSS) including the mathematical representationof a physiological model of respiratory control, including the effectsof chemical and musculature components of total respiratory drive and

FIG. 7 is a schematic flow chart of a method according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a schematic drawing of a mechanical ventilation system 10 forrespiration aid of an associated patient 5, P, the system being adaptedfor estimating the respiratory drive R_DRIVE of the patient.

The system comprises ventilator means 11, VENT capable of mechanicalventilating said patient with air and/or one or more medical gases, e.g.oxygen and/or nitrogen. Conventional ventilator systems currentlyavailable may be modified or adapted for working in the context of thepresent invention. Furthermore, control means 12, CON is comprised inthe system 10, the ventilator means 11 being controllable by saidcontrol means 10 by operational connection thereto, e.g. appropriatewirings and interfaces as it will be appreciated by the skilled personworking with mechanical ventilation.

Additionally, measurement means 11 a, M_G are arranged for measuring therespiratory feedback of said patient in the expired gas 6 in response tothe mechanical ventilation, e.g. respiratory frequency or fraction ofexpired carbon dioxide commonly abbreviated FECO₂, cf. list of somewell-known abbreviations below. The measurement means are shown asforming part of the ventilator means 11, but could alternatively form anindependent entity with respect to the ventilator means withoutsignificantly change the basic principle of the present invention. Themeasurement means M_G are capable of delivering first data D1 to thecontrol means 12 CON by appropriate connection, by wire, wirelessly orby other suitably data connection.

The control means 12 CON is also capable of operating the ventilationmeans by providing ventilatory assistance so that said patient 5 P is atleast partly breathing spontaneously, and, when providing suchventilatory assistance, the control means being capable of changing one,or more, volume and/or pressure parameters Vt_SET of the ventilatormeans so as to detect changes in the respiratory feedback in general ofthe patient by the measurement means M_G.

The control means is further being arranged for receiving second dataD2, preferably obtainable from blood analysis of said patient performedby blood measurement means M_B 20, the second data being indicative ofthe respiratory feedback in the blood of said patient, e.g. pHa, PACO2,PA02 etc. Notice that the by blood measurement means M_B 20 is notnecessarily comprised in the ventilator system 10 according to thepresent invention. Rather, the system 10 is adapted for receiving seconddata D2 from such an entity or device as schematically indicated by theconnecting arrow. It is however contemplated that a blood measurementmeans M_B could be comprised in the system 10 and integrated therein. Inthis embodiment, the mechanical ventilator system comprises at least theventilator means VENT 10, the measurement means M_G 11 a, and thecontrol means CON 12. The physiological model MOD is implemented on thecontrol means, e.g. in an appropriate computing entity or device.

In one variant of the invention, the second data D2 could be estimatedor guessed values being indicative of the respiratory feedback in theblood of said patient, preferably based on the medical history and/orpresent condition of the said patient. Thus, values from previously(earlier same day or previous days) could form the basis of suchestimated guess for second data D2.

The control means is adapted for using both the first data D1 indicativeof changes of respiratory feedback in expired air 6, and the second dataD2 indicative of the respiratory feedback in the blood 7, in aphysiological model MOD capable of estimating one, or more, componentsof the total respiratory drive R_DRIVE for the patient 6 asschematically indicated in the box 13.

The respiratory drive R_DRIVE may be outputted to an appropriatehuman-machine interface 13 for displaying the result, e.g. a computerwith a screen therefore. Alternatively or additionally, the respiratorydrive output R_DRIVE and/or its components, may be communicated to adecision support system DSS 14 for use in connection with mechanicalventilation of patients, optionally for treatment and/or diagnosticpurposes.

The principle of this invention is further exemplified in FIGS. 2 and 3.FIG. 2 illustrates an example of the structure a physiological modelused in the method. It consists of model components representing the gasexchange of the lungs and the acid-base chemistry of the blood,components representing the acid-base of cerebrospinal fluid (CSF) andthe resulting chemical respiratory drive, and the net effect of thischemical drive ventilation according to the action of respiratorymuscles. Some of these models exist in the scientific literature [3,4],which are hereby incorporated by reference in their entirety, and theadvantage of the present invention is not in the formulation of suchmodels as such but in their use, combined with changes in ventilation todetermine total respiratory drive, and/or any of the components relatedto chemical and muscular drive.

FIG. 3 illustrates the model simulated response of a patient to changesin ventilator support, in this case volume support, represented as thevolume of ventilation provided to the patient per breath (Vt), i.e. thevariable on the x-axis of each of the subfigures in FIG. 3. Alveolarventilation (VA) could be plotted instead of tidal ventilation with noapparent differences in the method. In particular it simulates theexpected respiratory frequency (3 a,d), arterial pH (3 b,e), and endtidal carbon dioxide (FE′CO₂) (3 c,f) levels at different levels ofvolume support (Vt). This response profile can be used to determine thetotal respiratory drive, and the components of chemical and muscularresponse. It is important to note that two factors separate thisapproach from those presented previously. The first is that no measureof the electrical activity of the diaphragm is used to assess themuscular drive to breathing. The second is that the simulated responseto changes in ventilator support due to chemical drive can be accountedfor by several physiological factors. This is only possible because ofthe physiological model, including factors contributing to the chemicaldrive describing: metabolism, and in particular the tissue production ofCO₂; the acid-base status of blood which modifies peripheralchemoreceptor drive; and the acid base status of CSF which modifiescentral chemoreceptor drive. These aspects have not been accounted forpreviously, e.g. US patent application 2010/0228142 which is based upondiaphragm electrical activity. FIGS. 3a, 3b and 3c of the presentapplication, illustrate two different situations of a normal (solidline) and reduced (dashed line) total respiratory drive. Reducing thetotal respiratory drive modifies the position of the curves and linesrepresenting these three variables. Estimation of the parallel shift ofthe three solid lines to the three dashed lines provides data whichenables estimation of changes in the total respiratory drive.

The apportionment of total respiratory drive to chemical and muscularcomponents can be seen as the difference between FIGS. 3a-c and 3d-f .In 3 a-c, i.e. left hand side of FIG. 3, the patient's muscle strengthis normal, and the patient can respond adequately to reduction in Vtsuch that respiratory frequency increases and pH and FE′CO₂ remainconstant. This pattern of response is consistent with the totalrespiratory drive being explained by changes in chemical response only.In this case the alveolar ventilation predicted by the chemical drivemodel (VAexp, FIG. 6) is equivalent to the alveolar ventilation of thepatient (VA, FIG. 6). FIGS. 3d-3f , i.e. the right hand side of FIG. 3illustrate the situation where patients muscle strength cannot respondadequately to reduction in volume support and respiratory frequencyincreases only partially, pH falls and FE′CO₂ increases. The alveolarventilation predicted by the chemical drive (VAexp, FIG. 6) cannot bemaintained by the muscles such that the true alveolar ventilation islower and as a consequence pH falls and FE′CO₂ increases. This can beimplemented by multiplying the alveolar ventilation predicted by thechemical model with a fraction (fM, FIG. 6) between 0 and 1, where 0represents no muscle action and 1 muscle action sufficient to allowalveolar ventilation consistent with the respiratory drive. Thequantification of the change in total respiratory drive and thecomponents due to chemical and muscular response can be performed eithervia shifts in the measured curves or by analysing the responsesillustrated in FIG. 3 using mathematical models, similar in structure toFIG. 2 and in details to FIG. 6. Estimation of mathematical modelparameters can then provide quantification of total respiratory driveand in addition chemical drive and/or muscular drive. It is thus to beunderstood that any combination of the total drive, the chemical drive(incl. sub-components) and the muscular drive (incl. sub-components) maybe provided as a result of applying the present invention as describedabove, the drive components not being provided as results may possiblybe applied as intermediate result(s), e.g. the total respiratory drivemay be an intermediate result for finding the components of musculardrive and/or chemical drive.

The overall principle of the method is then that changes in support modesettings which result in changes in tidal volume and respiratoryfrequency and or acid base status of blood or respiratory gasses can beused to estimate respiratory drive, and optionally apportion that tocomponents related to chemical and muscular drive.

The invention thus relates to a method for determining respiratory driveand apportioning this to components related to chemical and muscularresponse.

The invention comprises measuring the level of ventilation volume orpressure, and one or more of the following variables respiratoryfrequency, arterial blood pH or carbon dioxide level, and expiratorycarbon dioxide levels.

The invention further comprises changing ventilation volume or pressureand evaluating the changes in the following variables respiratoryfrequency, arterial blood pH or carbon dioxide level.

The method further comprises analysis of these data in terms ofmathematical models or curve shifts to determine respiratory drive.

The method further comprises analysis of these data in terms ofmathematical models or curve shifts to determine the component ofrespiratory drive due to chemical response.

The method further comprises that measurements of metabolism andacid-base status of the blood or CSF can be accounted for in thecomponent of respiratory drive due to chemical response.

The method further comprises analysis of these data in terms ofmathematical models or curve shifts to determine the component ofrespiratory drive due to response of the muscular system involved inbreathing.

Advantageously, the level of carbon dioxide in respiratory gas may beprovided by measurements of FECO₂, PECO₂, FE′CO₂, PE′CO₂ or otherequivalent measures available to the skilled person.

The present invention may be beneficially applied when the individual isa normal person, a person under mechanical ventilation in general, orsuffers from one or more respiratory diseases or abnormalities,including primary and secondary lung diseases, such as chronicobstructive pulmonary disease (COPD), acute lung injury, acuterespiratory distress syndrome, pulmonary edema, or asthma. Other relatedor similar diseases/conditions for which the present invention may beadvantageously applied are also contemplated.

The invention can be implemented by means of hardware, software,firmware or any combination of these. The invention or some of thefeatures thereof can also be implemented as software running on one ormore data processors and/or digital signal processors.

The individual elements of an embodiment of the invention may bephysically, functionally and logically implemented in any suitable waysuch as in a single unit, in a plurality of units or as part of separatefunctional units. The invention may be implemented in a single unit, orbe both physically and functionally distributed between different unitsand processors.

Although the present invention has been described in connection with thespecified embodiments, it should not be construed as being in any waylimited to the presented examples. The scope of the present invention isto be interpreted in the light of the accompanying claim set. In thecontext of the claims, the terms “comprising” or “comprises” do notexclude other possible elements or steps. Also, the mentioning ofreferences such as “a” or “an” etc. should not be construed as excludinga plurality. The use of reference signs in the claims with respect toelements indicated in the figures shall also not be construed aslimiting the scope of the invention. Furthermore, individual featuresmentioned in different claims, may possibly be advantageously combined,and the mentioning of these features in different claims does notexclude that a combination of features is not possible and advantageous.

It should be noted that embodiments and features described in thecontext of one of the aspects of the present invention also apply to theother aspects of the invention.

The invention will now be described in further details in the followingnon-limiting examples.

Example

FIGS. 4 and 5 exemplify the technique using data collected from twopatients (one for each figure). In FIG. 4, plots are shown of changes intidal volume (Vt) against A) respiratory frequency, B) end tidal CO₂ andC) arterial pH. The dashed curve in FIG. 4A represents the modelsimulated response of these variables assuming normal muscular andchemical response, normal values of metabolism, e.g. rate of tissue CO₂production, and normal values of the acid-base status of blood and CSF.Stars, solid circles, crosses, diagonal crosses, open circles andtriangles on plots 4A-C represent data collected at different values ofVt, with each symbol representing a different value of ventilatorsetting on the ventilator, Vt_SET. It should be noted this data has beencollected and plotted with volume as a variable, but in clinicalpractise the pressure is often applied as the variable instead. This ishowever equivalent as the skilled person will understand, and does notchange the overall principle and teaching of the present invention.

Solid curves on plots 4A-C represent model simulations when the chemicalresponse is adapted to the individual patient, but assuming normalmuscular response. This adaptation to chemical response includes: a)inputting the rate of CO₂ production into the physiological model forthat individual patient, where CO₂ production can be measured fromrespiratory gas composition and flow; b) inputting the acid-base statusof blood into the model and from this calculating the state of CSFacid-base status, where acid-base status is measured, for example, froma blood sample. In addition any factors in the response is not explainedby changes in CO₂ production or abnormal acid-base status are thenaccounted for by fitting the physiological mathematical model to themeasured data shown on FIG. 4A. This model fitting can be performedusing standard least-square techniques where model parameters such asthose describing thresholds or gains in central or peripheral chemicaldrive are adjusted until the model provides a best fit to the data asthe minimum sum of squared differences between model predictions andmeasured data. This model fitting can be performed for data collected ata single setting of mechanical ventilation, or over a data set collectedat several different settings as illustrated by each of the symbols onFIG. 4A.

In FIG. 5, plots are shown of changes in tidal volume (Vt) against (aand e) respiratory frequency, and (b and f) arterial pH, and (c and g)end tidal CO₂. The dashed curve in all subplots of FIG. 5 represent themodel simulated response of these variables assuming normal muscular andchemical response, normal values of metabolism, e.g. rate of tissue CO₂production, and normal values of the acid-base status of blood and CSF.Triangles, open circles, diagonal crosses, vertical crosses, diamondsand stars represent data collected or model simulations at differentvalues of Vt, with each symbol representing a different value ofventilator setting on the ventilator, Vt_SET. Measured data points areconnected with solid lines, and model simulated points are connectedwith dotted lines. It should be noted these data have been collected andplotted with volume as a variable as either tidal volume or alveolarventilation, but in clinical practise pressure is often applied as thevariable instead. This is however equivalent as the skilled person willunderstand, and does not change the overall principle and teaching ofthe present invention. Error bars are represented where points arerepeated measures. For FIGS. 5a-c these figures represent modelsimulations when the chemical response is adapted to the individualpatient, but assuming normal muscular response (fM=1). This adaptationto chemical response includes: a) inputting the rate of CO₂ productioninto the physiological model for that individual patient, where CO₂production can be measured from respiratory gas composition and flow; b)inputting the acid-base status of blood into the model and from thiscalculating the state of CSF acid-base status, where acid-base status ismeasured, for example, from a blood sample. In addition any factors inthe response is not explained by changes in CO₂ production or abnormalacid-base status are then accounted for by fitting the physiologicalmathematical model to the measured data shown on FIGS. 5 a-c. This modelfitting can be performed using standard least-square techniques wheremodel parameters such as those describing thresholds or gains in centralor peripheral chemical drive are adjusted until the model provides abest fit to the data as the minimum sum of squared differences betweenmodel predictions and measured data. This model fitting can be performedfor data collected at a single setting of mechanical ventilation, orover a data set collected at several different settings as illustratedby each of the symbols on FIGS. 5 a-c. It can be seen for this patientthat fitting the chemical drive model alone results in simulations(symbols connected with dotted lines) which match measurements (symbolsconnected with solid lines) very well for the highest 4 levels of Vt,i.e. for levels represented by triangles, open circles, diagonalcrosses, and vertical crosses. Data describing the lowest 2 levels of Vt(symbols starts and diamonds), where the patient is likely moststressed, are not described well by the chemical model with modelsimulated of respiratory frequency too high, model simulated pHa toohigh and model simulated FetCO2 too low.

FIG. 5 e-g includes model simulations (symbols connected with dottedlines) when the chemical response is adapted to the individual patient,along with adaptation to muscular response. It can be seen for thispatient that fitting the chemical drive model and muscular responseresults in simulations (symbols connected with dotted lines) which matchmeasurements (symbols connected with solid lines) at all levels of Vt.To do so the alveolar ventilation calculated by the chemical model ismodified by a constant fraction. This fraction is shown in FIG. 5d foreach of the values of Vt. For the highest 4 levels of Vt, i.e. forlevels represented by triangles, open circles, diagonal crosses, andvertical crosses the value of the fraction (fM) is 1, indicating nocorrection is required. For the lowest 2 levels of Vt (stars anddiamonds), where the patient is likely most stressed, the alveolarventilation calculated by the chemical model is reduced, requiring avalue of the fraction fM=approximately 0.7 to account for musclefatigue.

Patients

These cases represent mechanically ventilated patients admitted to anintensive care unit Informed consent was obtained and the study wasapproved by the local Ethics Committee.

Data Analysis and Results

The model of chemical drive was adapted to the patient to describe therespiratory frequency, end tidal CO2 and arterial pH changes followingchanges in Vt as described above accounting for CO₂ production,acid-base status in blood and CSF and by fitting the model to the datato estimate parameters describing the threshold and gain of centralchemoreceptor response. The shift illustrated by the arrow in FIG. 4a(labelled I) represents the change in chemical respiratory drive fromnormal seem in this patient due to all these factors in the mathematicalmodel.

Since the solid curves represent model simulations when the chemicalresponse is adapted to the individual patient, but assuming normalmuscular response, then the shift illustrated by the arrows in plots 4 band 4 c, and labelled II, represents changes in pH and PCO₂characteristic of muscle fatigue and hence reduced muscle drive. Theseshifts can be represented graphically as here, or by using values ofphysiological model parameters. These parameters can, for example,describe weighting of the calculated chemical drive so as to reduce theeffect of chemical response.

The differences between model simulations (symbols connected with dashedlines) illustrated in FIGS. 5e-g and the dashed lines on these figuresrepresent the changes in chemical respiratory drive from normal and allother factors previously discussed plus the effects of muscle fatigueseen in this patient. The difference between model simulations (symbolsconnected by dotted lines) in FIGS. 5 a-c and FIGS. 5 e-g represents thedifferences characteristic of muscle fatigue and hence reduced muscledrive. These differences are quantified in this figure by estimating thefactor fM which weighs the expected alveolar ventilation given thechemical drive (VAexp, FIG. 6) to give the patients true alveolarventilation given their muscular response (VA, FIG. 6).

Conclusion

In these examples, it is shown that data describing the response tochanges in respiratory tidal volume can be used to identify changes inrespiratory drive, including those that can be apportioned to changes inchemical and muscular response and that chemical drive can be measuredcomponents accounting for metabolism and acid-base status and modelparameters describing regulation of chemoreceptors.

FIG. 6 illustrates the set of mathematical model components of adecision support system (DSS) including the mathematical representationin the form of physiological model of respiratory control and musclefunction that may be applied in the context of the present invention.For further background on these models, the skilled person is referredto references [1-6] listed below, which are hereby incorporated byreference in their entirety.

The DSS includes models of: pulmonary gas exchange (A); acid-base statusand oxygenation of blood (B); acid-base status of CSF (C); circulationand blood in arterial and mixed venous pools (D); interstitial fluid andtissue buffering, and metabolism (E); chemoreflex model of respiratorycontrol (F); muscular function (G); and ventilation (H).

FIG. 6 illustrates the set of mathematical model components of INVENTincluding the mathematical representation of respiratory control (A-H).FIG. 6A illustrates the structure of the model of ventilation andpulmonary gas exchange. FIG. 6B illustrates the structure of the modelof oxygenation and acid-base status in the blood. FIG. 6 C illustratesDuffin's model of CSF with appropriate model constants [3, 4]. Thismodel includes mass-action equations describing water, phosphate andalbumin dissociation plus the formation of bicarbonate and carbonate,and an equation representing electrical neutrality (equations 1-6). Inaddition, equation (7) is used to describe the equilibration of PCO₂with arterial blood across the blood-brain barrier. Equation (8) is amodification to Duffin's model which allows calibration of the CSF toconditions where blood bicarbonate, and hence buffer base (BB) or strongion difference (SID) are modified, such as metabolic acidosis whereblood bicarbonate is reduced, or chronic lung disease where bloodbicarbonate is increased.

The model illustrated in FIG. 6 includes compartments representing CO₂transport and storage including the arterial and venous compartments,and circulation represented as cardiac output (Q) (FIG. 5D).

FIG. 6E illustrates the model of interstitial fluid and tissuebuffering, and metabolism included in the system. This includes oxygenconsumption (VO₂) and carbon dioxide production (VCO₂).

FIG. 6F illustrates the model of respiratory control of Duffin, i.e.equations 9-12. Alveolar ventilation is modeled as a peripheral andcentral chemoreflex response to arterial and cerebrospinal fluid (CSF)hydrogen ion concentration ([H⁺a] and [H⁺csf]) plus wakefulness drive.Equation (9) describes the peripheral drive (Dp) as a linear function ofthe difference between [H⁺a] and the peripheral threshold (Tp). Theslope of this function (Sp) represents the sensitivity of the peripheralchemoreceptors.

Equation (11) describes central drive (Dc) as a linear function of thedifference between [H⁺csf] and the central threshold (Tc). The slope ofthis function (Sc) represents the sensitivity of central chemoreceptors.Equation (12) describes the expected alveolar ventilation as the sum ofthe two chemoreflex drives and the wakefulness drive (Dw).

FIG. 6G represents the muscular action on alveolar ventilation. Thecalculated alveolar ventilation from the respiratory control equations(FIG. 6F) is scaled according to a constant (0<fM≦1) to calculate thealveolar ventilation applied by the muscles. A value of fM<1 illustratesthat the muscle cannot deliver the respiratory drive calculated by thechemical control model.

FIG. 6H, equation 14, describes the minute ventilation as alveolarventilation plus ventilation of the dead space, that is equal to theproduct of tidal volume (Vt) and respiratory frequency (f).

The model described above can be used to simulate respiratory control.The model enables simulation of the control of alveolar ventilationtaking into account pulmonary gas exchange, blood and CSF acid-basestatus, circulation, tissue and interstitial buffering, and metabolism.

FIG. 7 is a schematic flow chart of a method according to the invention.The invention thus relates to a method for operating a mechanicalventilation system 10 for respiration aid of an associated patient 5, P,the method being adapted for estimating the respiratory drive R_drive ofsaid patient, the method comprising:

-   -   S1 providing ventilator means VENT capable of mechanical        ventilating said patient with air and/or one or more medical        gases,    -   S2 providing control means CON, the ventilator means being        controllable by said control means by operational connection        thereto, and    -   S3 providing measurement means M_G arranged for measuring the        respiratory feedback of said patient in the expired gas in        response to the mechanical ventilation, the measurement means        being capable of delivering first data D1 to said control means,        wherein the control means is capable of operating the        ventilation means by providing ventilatory assistance so that        said patient is at least partly breathing spontaneously, and,        when providing such ventilatory assistance, the control means        being capable of changing one, or more, volume and/or pressure        parameters Vt_SET of the ventilator means so as to detect        changes in the respiratory feedback of said patient by the        measurement means,        the control means further being arranged for receiving second        data (D2), preferably obtainable from blood analysis of said        patient, said second data being indicative of the respiratory        feedback in the blood of said patient,        the control means being adapted for:    -   applying the first data D1 indicative of changes of respiratory        feedback in expired air, and    -   applying the second data D2 indicative of the respiratory        feedback in the blood,        in a physiological model MOD capable of estimating one, or more,        components, R_MUSC and/or R_CHEM, of the total respiratory        drive, R_DRIVE, for the patient 5, P.

GLOSSARY

-   CSF Cerebral spinal fluid-   Vt Respiratory volume in a single breath, tidal volume-   Vt_SET Respiratory volume settings for mechanical ventilation, tidal    volume-   FECO₂ Fraction of carbon dioxide in expired gas.-   FE′CO₂ Fraction of carbon dioxide in expired gas at the end of    expiration.-   PECO₂ Partial pressure of carbon dioxide in expired gas.-   PE′CO₂ Partial pressure of carbon dioxide in expired gas at the end    of expiration.-   RR respiratory frequency (RR) or, equivalently, duration of breath    (including duration of inspiratory or expiratory phase)-   pHa Arterial blood pH-   PaCO2 Pressure of carbon dioxide level,-   SaO2 Oxygen saturation of arterial blood-   PpO2 Pressure of oxygen in arterial blood

In short, the present invention relates to a system 10 and acorresponding method for estimating the respiratory drive, R_DRIVE, ofmechanically ventilated patients, and for preferably apportioning thisrespiratory drive into one, or more, components related to the chemicaldrive—i.e. the drive due to the chemoreceptor response- and/or themuscular drive—i.e. the contraction of respiratory muscles, for examplethe diaphragm. The principle of the invention is that respiratory drivecan be obtained from measuring the patient's response to small changesin mechanical ventilation settings, Vt_SET, and that this can beapportioned into chemical and/or muscular effects depending upon thechanges in respiratory frequency, and/or arterial or end tidal CO₂levels, and/or arterial blood pH, as indicated in FIG. 1.

REFERENCES

-   1. The Acute Respiratory Distress Syndrome (ARDS) Network (2000)    Ventilation with lower tidal volumes as compared with traditional    tidal volumes for acute lung injury and the acute respiratory    distress syndrome. N Engl. J Med. 342:1301-1308.-   2. L. Brochard and A. W. Thille, “What is the proper approach to    liberatng the weak from mechanical ventilation?,” Critical Care,    vol. 37, pp. 5410-5415, 2009.-   3. Duffin, J. “The role of the central chemoreceptors: A modeling    perspective.” Respiratory Physiology and Neurobiology 173 (2010):    230-243.    -   This reference is particularly relevant for the models on        acid-base status of CSF (C), and respiratory drive (F) as shown        in FIG. 6.-   4. Duffin, J. “Role of acid-base balance in the chemoreflex control    of breathing.” J Appl Physiol 99 (2005): 2255-2265.    -   This reference is also particularly relevant for the models on        acid-base status of CSF (C) and respiratory drive (F) as shown        in FIG. 6.-   5. S. E. Rees, C. Allerød, D. Murley, Y. Zhao, B. W. Smith, S.    Kjaergaad, P. Thorgaad and S. Andreassen, “Using physiological    models and decision theory for selecting appropriate ventilator    settings,” Journal of Clinical Monitoring and Computing, vol. 20,    pp. 421-429, 2006.-   6. S. E. Rees, “The Intelligent Ventilator (INVENT) project: The    role of mathematical models in translating physiological knowledge    into clinical practice,” Computer Methods and Programs in    Biomedicine, vol. 104S, pp. S1-S29, 2011.    -   This reference is particularly relevant for the models of        pulmonary gas exchange (A); acid-base status and oxygenation of        blood (B); circulation and blood in arterial and mixed venous        pools (D); interstitial fluid and tissue buffering, and        metabolism (E), as shown in FIG. 6.

All patent and non-patent references cited in the present application,are hereby incorporated by reference in their entirety.

Annex with Embodiments

In a separate aspect, the invention relates to the following embodimentsfound in the priority founding Danish patent application PA 2013 70283:

1. A mechanical ventilation system (10) for respiration aid of anassociated patient (5, P), the system being adapted for estimating therespiratory drive (R_drive) of said patient, the system comprising:

-   -   ventilator means (11, VENT) capable of mechanical ventilating        said patient with air and/or one or more medical gases,    -   control means (12, CON), the ventilator means being controllable        by said control means by operational connection thereto, and    -   measurement means (11 a, M_G) arranged for measuring the        respiratory feedback of said patient in the expired gas (6) in        response to the mechanical ventilation, the measurement means        being capable of delivering first data (D1) to said control        means,        wherein the control means is capable of operating the        ventilation means by providing ventilatory assistance so that        said patient is at least partly breathing spontaneously, and,        when providing such ventilatory assistance, the control means        being capable of changing one, or more, volume and/or pressure        parameters (Vt_SET) of the ventilator means so as to detect        changes in the respiratory feedback of said patient by the        measurement means,        the control means further being arranged for receiving second        data (D2), preferably obtainable from blood analysis of said        patient, said second data being indicative of the respiratory        feedback in the blood of said patient,        the control means being adapted for using:    -   the first data (D1) indicative of changes of respiratory        feedback in expired air (6), and    -   the second data (D2) indicative of the respiratory feedback in        the blood (7),        in a physiological model (MOD) capable of estimating the total        respiratory drive (R_DRIVE) for the patient.        2. The mechanical ventilation system according to embodiment 1,        wherein the physiological model (MOD) comprises a component of        the total respiratory drive being indicative of muscular        response (R_MUSC).        3. The mechanical ventilation system according to embodiment 1        or 2, wherein the physiological model (MOD) comprises a        component of the total respiratory drive being indicative of        chemical response (R_CHEM), preferably a subcomponent indicative        of the central chemical response and a subcomponent indicative        of the peripheral chemical response.        4. The mechanical ventilation system according to any of        embodiments 1-3, wherein the control means is arranged for        estimating both the muscular response (R_MUS) and chemical        response (R_CHEM) forming part of the total respiratory drive        (R_DRIVE).        5. The mechanical ventilation system according to any of        embodiments 1-4, wherein the control means is arranged for        estimating the muscular response (R_MUS) and chemical response        (R_CHEM) by initially assuming one of the two responses;        muscular response (R_MUS) or chemical response (R_CHEM), being a        certain approximately constant level, preferably a normal level        for said patient, and then subsequently iteratively solving for        the other response.        6. The mechanical ventilation system according to embodiment 1,        wherein the second data (D2) used in the physiological model        (MOD) is indicative for oxygenation and/or acid-base status of        the blood, preferably being related to the influence of the        acid-base status on the cerebrospinal fluid (CSF).        7. The mechanical ventilation system according to embodiment 1,        wherein the second data (D2) used in the physiological model        (MOD) is indicative for the metabolism of said patient,        preferably the tissue production of carbon dioxide (CO₂).        8. The mechanical ventilation system according to any of        embodiment 1-7, wherein the physiological model (MOD) capable of        estimating the total respiratory drive (R_DRIVE) for the patient        is operationally connected to a medical decision support system        (DSS), preferably for application in mechanical ventilation.        9. The mechanical ventilation system according to embodiment 1,        wherein the measurement means (M_G) is arranged for measuring        one or more of the following parameters consisting of:        respiratory frequency (RR) or, equivalently, duration of breath        (including duration of inspiratory or expiratory phase), and        expiratory carbon dioxide levels (FECO₂), fraction of carbon        dioxide in expired gas at the end of expiration, (FE′CO₂),        partial pressure of carbon dioxide in expired gas (PECO₂),        partial pressure of carbon dioxide in expired gas at the end of        expiration (PE′CO₂), or equivalents thereof and/or combinations        thereof.        10. The mechanical ventilation system according to 1, wherein        the second data (D2), which is preferably obtainable from blood        analysis (M_B) of said patient (P), is one or more parameters        consisting of: arterial blood pH (pHa), pressure of carbon        dioxide level (PaCO2), optionally measured transcutaneously        (PtcC02), oxygen saturation of arterial blood (SaO2), pressure        of oxygen in arterial blood (PpO2), or equivalents thereof        and/or combinations thereof.        11. The mechanical ventilation system according to embodiment 1,        wherein the respiratory drive is estimated without using a        measurement of the electrical activity of the diaphragm of the        patient.        12. The mechanical ventilation system according to embodiment 1,        wherein the control means (CON) is capable of changing the level        from one value to another value in one, or more, volume and/or        pressure parameters of the ventilator means (Vt_SET) so as to        detect the subsequent changes in the respiratory feedback of        said patient by the measurement means.        13. The mechanical ventilation system according to embodiment 1,        wherein the control means is capable of performing a change in        one, or more, volume and/or pressure parameters of the        ventilator means (Vt_SET) so as to detect associated changes in        the respiratory feedback of said patient by the measurement        means while performing said change.        14. The mechanical ventilation system according to embodiment 1,        wherein the control means is capable of changing one, or more,        volume and/or pressure parameters of the ventilator means by        changing the inspiratory volume (Vt_SET) and/or the inspiratory        pressure set by the ventilator means.        15. A method for operating a mechanical ventilation system for        respiration aid of an associated patient, the method being        adapted for estimating the respiratory drive (R_drive) of said        patient, the method comprising:    -   providing ventilator means (VENT) capable of mechanical        ventilating said patient with air and/or one or more medical        gases,    -   providing control means (CON), the ventilator means being        controllable by said control means by operational connection        thereto, and    -   providing measurement means (M_G) arranged for measuring the        respiratory feedback of said patient in the expired gas in        response to the mechanical ventilation, the measurement means        being capable of delivering first data (D1) to said control        means,        wherein the control means is capable of operating the        ventilation means by providing ventilatory assistance so that        said patient is at least partly breathing spontaneously, and,        when providing such ventilatory assistance, the control means        being capable of changing one, or more, volume and/or pressure        parameters (Vt_SET) of the ventilator means so as to detect        changes in the respiratory feedback of said patient by the        measurement means,        the control means further being arranged for receiving second        data (D2), preferably obtainable from blood analysis of said        patient, said second data being indicative of the respiratory        feedback in the blood of said patient,        the control means being adapted for:    -   applying the first data (D1) indicative of changes of        respiratory feedback in expired air, and    -   applying the second data (D2) indicative of the respiratory        feedback in the blood,        in a physiological model (MOD) capable of estimating the total        respiratory drive (R_DRIVE) for the patient.        16. A computer program product being adapted to enable a        computer system comprising at least one computer having data        storage means in connection therewith to control a ventilation        system (10) according to embodiment 15.

1. A mechanical ventilation system for respiration aid of an associatedpatient, the system being adapted for estimating one, or more,components of the respiratory drive of said patient, the systemcomprising: a ventilator configured for mechanical ventilation of saidpatient with air and/or one or more medical gases, a controller that isoperably connected to said ventilator, and a detector configured tomeasure the respiratory feedback of said patient in the expired gas inresponse to the mechanical ventilation, the detector being capable ofdelivering first data to said controller, wherein the controller iscapable of operating the ventilator by providing ventilatory assistanceso that said patient is at least partly breathing spontaneously, and,when providing such ventilatory assistance, the controller is capable ofchanging one, or more, volume and/or pressure parameters of theventilator so as to detect changes in the respiratory feedback of saidpatient by the detector, the controller further being arranged forreceiving second data, from a blood analysis of said patient, saidsecond data being indicative of the respiratory feedback in the blood ofsaid patient, the controller being adapted for using: the first dataindicative of changes of respiratory feedback in expired air, and thesecond data indicative of the respiratory feedback in the blood, in aphysiological model, which estimates one, or more, components of thetotal respiratory drive for the patient. 2-18. (canceled)
 19. Themechanical ventilation system according to claim 1, wherein thephysiological model (MOD) comprises a component of the total respiratorydrive that is indicative of muscular response (R_MUSC).
 20. Themechanical ventilation system according to claim 1, wherein the detectorand the controller are further configured to measure an indication ofmuscular response (R_MUSC).
 21. The mechanical ventilation systemaccording to claim 1, wherein the physiological model (MOD) comprises acomponent of the total respiratory drive that is indicative of achemical response (R_CHEM).
 22. The mechanical ventilation systemaccording to claim 1, wherein the controller is configured to estimateboth a muscular response (R_MUS) and a chemical response (R_CHEM)forming part of the total respiratory drive (R_DRIVE).
 23. Themechanical ventilation system according to claim 1, wherein thecontroller is configured to estimate a muscular response (R_MUS) and achemical response (R_CHEM) by initially assuming one of the tworesponses; muscular response (R_MUS) or chemical response (R_CHEM),being a certain approximately constant level, or a normal level for saidpatient, and then subsequently iteratively solving for the otherresponse.
 24. The mechanical ventilation system according to claim 22,wherein the muscular response is initially assumed constant, or at anormal level for said patient, and the chemical response is estimated,the estimated chemical response being subsequently applied for modellinga respiratory feedback to be compared with a measured respiratoryfeedback of the patient, any deviation therebetween being a measure foran inadequate response capability of the patient.
 25. The mechanicalventilation system according to claim 1, wherein the second data (D2)used in the physiological model (MOD) is indicative for oxygenationand/or acid-base status of the blood, or is related to the influence ofthe acid-base status on the cerebrospinal fluid (CSF).
 26. Themechanical ventilation system according to claim 1, wherein the seconddata (D2) used in the physiological model (MOD) is indicative for themetabolism of said patient, or the tissue production of carbon dioxide(CO₂).
 27. The mechanical ventilation system according to claim 1,wherein the physiological model (MOD) capable of estimating one, ormore, components of the total respiratory drive (R_DRIVE) for thepatient is operationally connected to a medical decision support system(DSS), for application in mechanical ventilation.
 28. The mechanicalventilation system according to claim 1, wherein the detector (M_G) isconfigured to measure one or more of the following parameters:respiratory frequency (RR) or, equivalently, duration of breath(including duration of inspiratory or expiratory phase), and expiratorycarbon dioxide levels (FECO₂), fraction of carbon dioxide in expired gasat the end of expiration, (FE′CO₂), partial pressure of carbon dioxidein expired gas (PECO₂), or partial pressure of carbon dioxide in expiredgas at the end of expiration (PE′CO₂), or equivalents thereof and/orcombinations thereof.
 29. The mechanical ventilation system according to1, wherein the second data (D2), which is from a blood analysis (M_B) ofsaid patient (P), comprises one or more parameters of: arterial blood pH(pHa), pressure of carbon dioxide level (PaCO2), optionally measuredtranscutaneously (PtcC02), oxygen saturation of arterial blood (SaO2),or pressure of oxygen in arterial blood (PpO2), or equivalents thereofand/or combinations thereof.
 30. The mechanical ventilation systemaccording to claim 1, wherein the respiratory drive is estimated withoutusing a measurement of the electrical activity of the diaphragm of thepatient.
 31. The mechanical ventilation system according to claim 1,wherein the controller (CON) is configured to change the level from onevalue to another value in one, or more, volume and/or pressureparameters of the ventilator means (Vt_SET) so as to detect thesubsequent changes in the respiratory feedback of said patient by thedetector.
 32. The mechanical ventilation system according to claim 1,wherein the controller is configured to change in one, or more, volumeand/or pressure parameters of the ventilator means (Vt_SET) so as todetect associated changes in the respiratory feedback of said patient bythe detector while performing said change.
 33. The mechanicalventilation system according to claim 1, wherein the controller iscapable of changing one, or more, volume and/or pressure parameters ofthe ventilator by changing the inspiratory volume (Vt_SET) and/or theinspiratory pressure set by the ventilator.
 34. A method for operating amechanical ventilation system for respiration aid of an associatedpatient, the method being adapted for estimating the respiratory drive(R_drive) of said patient, the method comprising: providing a ventilator(VENT) capable of mechanical ventilating said patient with air and/orone or more medical gases, providing a controller (CON), the ventilatorbeing controllable by said controller by operational connection thereto,and providing a detector (M_G) configured to measure the respiratoryfeedback of said patient in the expired gas in response to themechanical ventilation, the detector being capable of delivering firstdata (D1) to said controller, wherein the controller is capable ofoperating the ventilator by providing ventilatory assistance so thatsaid patient is at least partly breathing spontaneously, and, whenproviding such ventilatory assistance, the controller is capable ofchanging one, or more, volume and/or pressure parameters (Vt_SET) of theventilator so as to detect changes in the respiratory feedback of saidpatient by the detector, the controller further being arranged forreceiving second data (D2), from a blood analysis of said patient, saidsecond data being indicative of the respiratory feedback in the blood ofsaid patient, the controller being adapted for: applying the first data(D1) indicative of changes of respiratory feedback in expired air, andapplying the second data (D2) indicative of the respiratory feedback inthe blood, in a physiological model (MOD) capable of estimating one, ormore, components (R_MUSC, R_CHEM) of the total respiratory drive(R_DRIVE) for the patient.
 35. A computer program product being adaptedto enable a computer system comprising at least one computer having datastorage in connection therewith to control a ventilation systemaccording to claim 34.